{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:37:09Z","timestamp":1792103829127,"version":"4.4.0"},"reference-count":35,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,4,27]],"date-time":"2020-04-27T00:00:00Z","timestamp":1587945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP17fk0210306"],"award-info":[{"award-number":["JP17fk0210306"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP19fk0210034"],"award-info":[{"award-number":["JP19fk0210034"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lifestyle changes have led to an increase in the number of patients with nonalcoholic fatty liver disease (NAFLD). However, the effects of NAFLD-associated single-nucleotide gene polymorphisms (SNPs) in HBV-infected patients have not been adequately investigated. Methods: We investigated the association of the NAFLD-related SNPs patatin-like phospholipase domain-containing protein 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13; rs72613567, rs6834314 and rs62305723), membrane-bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) and glucokinase regulatory protein (GCKR; rs1260326) with the presence of histologically proven hepatic steatosis (HS) in HBV-infected patients (n = 224). We also investigated tolloid-like 1 (TLL1) SNP (rs17047200), which has been reported to be involved in the disease progression in Japanese NAFLD patients, and evaluated the association of HS and various SNPs with the treatment efficacy of pegylated-interferon (PEG-IFN) monotherapy following nucleotide\/nucleoside (NA) treatment (NA\/PEG-IFN sequential therapy; n = 64). Among NAFLD-associated SNPs evaluated, only the PNPLA3 SNP was significantly associated with the presence of hepatic steatosis in a total of 224 HBV-infected patients (P = 1.0 \u00d7 10\u22124). Regarding the sequential therapy, PNPLA3 SNP and TLL1 SNP were related to the treatment efficacy, and patients without minor alleles of these SNPs showed favorable results with a high virologic response and significant reduction in their HBsAg titer. A multivariate analysis showed that HBeAg positivity (odds ratio 5.810, p = 0.016) and the absence of a risk allele in PNPLA3 and TLL1 SNPs (odds ratio 8.664, p = 0.0042) were significantly associated with treatment efficacy. The PNPLA3 SNP might be associated with the presence of HS, and the combination of the PNPLA3 and TLL1 SNPs might be related to the efficacy of PEG-IFN monotherapy following NA treatment.<\/jats:p>","DOI":"10.3390\/ijms21093089","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T05:05:32Z","timestamp":1588050332000},"page":"3089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Possible Relevance of PNPLA3 and TLL1 Gene Polymorphisms to the Efficacy of PEG-IFN Therapy for HBV-Infected Patients"],"prefix":"10.3390","volume":"21","author":[{"given":"Hirayuki","family":"Enomoto","sequence":"first","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Aizawa","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunihiro","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Sakai","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Yoh","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Takata","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihisa","family":"Yuri","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyohei","family":"Kishino","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Shimono","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Ishii","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Takashima","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"},{"name":"Ultrasound Imaging Center, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Nishikawa","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"},{"name":"Center for Clinical Research and Education, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Iwata","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Iijima","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"},{"name":"Ultrasound Imaging Center, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Nishiguchi","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1002\/hep.29800","article-title":"Update on prevention; diagnosis; and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance","volume":"67","author":"Terrault","year":"2018","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2017). EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol., 67, 370\u2013398.","DOI":"10.1016\/j.jhep.2017.03.021"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12072-015-9675-4","article-title":"Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update","volume":"10","author":"Sarin","year":"2016","journal-title":"Hepatol. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) (2016). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol., 64, 1388\u20131402.","DOI":"10.1016\/j.jhep.2015.11.004"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.jhep.2014.05.045","article-title":"Prevalence and causes of elevated serum aminotransferase levels in a population-based cohort of persons with chronic hepatitis B virus infection","volume":"61","author":"Spradling","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e3565","DOI":"10.1097\/MD.0000000000003565","article-title":"Relationship Between Hepatic Steatosis and the Elevation of Aminotransferases in HBV-Infected Patients With HBe-Antigen Negativity and a Low Viral Load","volume":"95","author":"Enomoto","year":"2016","journal-title":"Medicine (Baltimore)"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1096406","DOI":"10.1155\/2017\/1096406","article-title":"The Effect of Hepatosteatosis on Response to Antiviral Treatment in Patients with Chronic Hepatitis B: A Meta-Analysis","volume":"2017","author":"Zhu","year":"2017","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.jhep.2017.09.003","article-title":"Genetics and epigenetics of NAFLD and NASH: Clinical impact","volume":"68","author":"Eslam","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e3001","DOI":"10.1002\/jgm.3001","article-title":"Association of PNPLA3 rs738409 polymorphism with liver steatosis but not with cirrhosis in patients with HBV infection: Systematic review with meta-analysis","volume":"20","author":"Ghalamkari","year":"2018","journal-title":"J Gene Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1002\/hep.26445","article-title":"Patatin-like phospholipase domain-containing 3 I148M affects liver steatosis in patients with chronic hepatitis B","volume":"58","author":"Valenti","year":"2013","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1007\/s10620-015-3716-7","article-title":"Patatin-Like Phospholipase Domain-Containing 3 I148M Variant Is Associated with Liver Steatosis and Fat Distribution in Chronic Hepatitis B","volume":"60","author":"Zampino","year":"2015","journal-title":"Dig. Dis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/jvh.12035","article-title":"Hepatitis C virus diversity and hepatic steatosis","volume":"20","author":"Roingeard","year":"2013","journal-title":"J. Viral Hepat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1111\/apt.12717","article-title":"Review article: Genetic factors that modify the outcome of viral hepatitis","volume":"39","author":"Scherzer","year":"2014","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S69","DOI":"10.1016\/j.jhep.2014.08.003","article-title":"Facts and fictions of HCV and comorbidities: Steatosis, diabetes mellitus, and cardiovascular diseases","volume":"61","author":"Negro","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Adinolfi, L.E., Rinaldi, L., Guerrera, B., Restivo, L., Marrone, A., Giordano, M., and Zampino, R. (2016). NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17060803"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/jgh.12700","article-title":"Hepatitis B virus infection and metabolic syndrome: Fact or fiction?","volume":"30","author":"Wang","year":"2015","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s00535-017-1414-2","article-title":"Clinical strategy of diagnosing and following patients with nonalcoholic fatty liver disease based on invasive and noninvasive methods","volume":"53","author":"Yoneda","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1056\/NEJMoa1712191","article-title":"A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease","volume":"378","author":"Cheng","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/hep.30350","article-title":"17-Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease","volume":"69","author":"Ma","year":"2019","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/hep.30799","article-title":"High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase\u2013Lowering Effect of a HSD17B13 Variant","volume":"71","author":"Nordestgaard","year":"2020","journal-title":"Hepatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1007\/s00535-013-0884-0","article-title":"Thrombocytopenia in pegylated interferon and ribavirin combination therapy for chronic hepatitis C","volume":"49","author":"Aizawa","year":"2014","journal-title":"J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1053\/j.gastro.2017.01.041","article-title":"Japanese Genome-Wide Association Study Group for Viral Hepatitis. Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection","volume":"152","author":"Matsuura","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s00535-018-1526-3","article-title":"TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy","volume":"54","author":"Iio","year":"2019","journal-title":"J. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1007\/s00535-017-1372-8","article-title":"Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease","volume":"53","author":"Seko","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00535-017-1360-z","article-title":"Combinational use of hepatitis B viral antigens predicts responses to nucleos(t)ide analogue\/peg-interferon sequential therapy","volume":"53","author":"Matsumoto","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1111\/hepr.13050","article-title":"Sequential therapy involving an early switch from entecavir to pegylated interferon-\u03b1 in Japanese patients with chronic hepatitis B","volume":"48","author":"Enomoto","year":"2018","journal-title":"Hepatol. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1007\/s00535-019-01594-6","article-title":"Nonalcoholic fatty liver disease is associated with lower hepatitis B viral load and antiviral response in pediatric population","volume":"54","author":"Wang","year":"2019","journal-title":"J. Gastroenterol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1053\/j.gastro.2011.11.025","article-title":"Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B","volume":"142","author":"Sonneveld","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wei, L., Wedemeyer, H., Liaw, Y.F., Chan, H.L., Piratvisuth, T., Marcellin, P., Jia, J., Tan, D., Chow, W.C., and Brunetto, M.R. (2018). No association between IFNL3 (IL28B) genotype and response to peginterferon alfa-2a in HBeAg-positive or -negative chronic hepatitis B. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199198"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1111\/jvh.13155","article-title":"TLL1 variants do not predict hepatocellular carcinoma development in HCV cirrhotic patients treated with direct-acting antivirals","volume":"26","author":"Degasperi","year":"2019","journal-title":"J. Viral. Hepat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1111\/liv.12695","article-title":"The impact of PNPLA3 (rs738409 C>G) polymorphisms on liver histology and long-term clinical outcome in chronic hepatitis B patients","volume":"35","author":"Brouwer","year":"2015","journal-title":"Liver Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1002\/hep.30857","article-title":"Nonalcoholic Steatohepatitis Is Associated With Liver-Related Outcomes and All-Cause Mortality in Chronic Hepatitis B","volume":"71","author":"Choi","year":"2020","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/jgh.13857","article-title":"Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017-Part 1: Definition; risk factors and assessment","volume":"33","author":"Wong","year":"2018","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1053\/j.gastro.2012.02.007","article-title":"High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load","volume":"142","author":"Tseng","year":"2012","journal-title":"Gastroenterology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/9\/3089\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:09:18Z","timestamp":1760364558000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/9\/3089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,27]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ijms21093089"],"URL":"https:\/\/doi.org\/10.3390\/ijms21093089","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,27]]}}}